A Study of Chlorophyllin or Placebo With Standard Treatment for Late Radiation Induced Luminal Gastrointestinal Tract Bleeding

Participants randomized to this arm will receive oral sodium copper chlorophyllin (CHL) 500 mg once daily for 3 months in addition to standard medical management for late radiation-induced gastrointestinal bleeding. Standard care may include supportive measures such as blood transfusions, hematinics, laxatives, tranexamic acid, sucralfate or enterofoam enema, and optimization of anticoagulant therapy as clinically indicated. Participants will be followed for up to 2 years.

Sodium copper chlorophyllin 500 mg oral tablet administered once daily for 3 months in addition to standard medical management for late radiation-induced gastrointestinal bleeding. Participants are randomized to receive either chlorophyllin or a matching placebo in a double-blind manner.

Participants randomized to this arm will receive matching placebo tablets once daily for 3 months in addition to standard medical management for late radiation-induced gastrointestinal bleeding. The placebo is identical in appearance, packaging, and labeling to the investigational product to maintain blinding. Participants will receive the same standard medical management and follow-up schedule as the experimental arm.

A matching placebo tablet identical in appearance, packaging, and administration schedule to the chlorophyllin tablet. Participants will receive one placebo tablet orally once daily for 3 months in addition to standard medical management. The placebo is designed to maintain blinding in this double-blind, randomized trial.

Grade 2 or higher anemia (CTCAE anemia version 5) due to uncontrolled bleeding defines failure of intervention. This will be actively evaluated at 1,3 and 6 months and for the intervention to be successful, Hb should be >/=10gm/dl (at the same lab, where baseline Hb was evaluated) at 6 months from randomization. Interim Hb levels for unplanned patients visits and 1, 3 months will also be counted, where if Hb <8gm/gl, then the intervention will be deemed unsuccessful without waiting for 6 months and patient will be managed as per institutional protocol. Patients may still be followed up for recording institutional practice (interventions) and outcomes till 2 years follow up is completed.

Additionally, patients may be assessed with exploratory study specific objective + subjective criteria's at each visits as below:

Assessment Item Pre - post effectiveness definition per item

1. Amount of bleeding Example: Small streak/ few drops /clots and fresh blood/copious amount in more than 50% episodes. Mandatory improvement of amount and percentage bleeding episodes per day in last one week.
2. Frequency of bleeding Daily/alt day/ weekly once /occasionally: once in two weeks or less. Mandatory improvement in frequency estimated in last one week.
3. Associated symptoms (pain/tenusmus/other) with CTCAE grade Optional improvement in CTCEA grade.
4. CTCAE grade Bleeding Should not deteriorate (intervention should be started only after stabilizing HB above 10 g/dl)
5. CTCAE grade Anemia Should not deteriorate (intervention should be started only after stabilizing HB above 10 g/dl)
6. Surgical Intervention Must not have been required (needed)

Patients identified to be occult blood positive in stool at randomization and their conversion to test negative at Visit 2-6, may be estimated as a surrogate for subclinical mucosal healing shadowing clinical response. These may further be correlated with clinical response, QoL scores and endoscopic response assessment.

To assess improvements in related gastrointestinal symptoms such as pain, urgency, frequency, tenesmus, diarrhea and other additional associated late toxicity symptoms, PROMs following treatment and their inter-correlations.

To document and quantify endoscopic mucosal healing or improvement using RTOG grading where, Grade 0: No change or just congested mucosa, Grade 1: Minor changes, such as microulceration or mild telangiectasia (small, dilated blood vessels), Grade 2: Superficial ulceration (>1cm2) or significant telangiectasia, Grade 3: Deep ulceration, severe congestion, or marked bleeding and Grade 4: Necrosis, fistula, or perforation This is derived from OMED scoring coorelated with RTOG/EORTC morbidity scoring

It includes iron studies (serum iron, ferritin, total iron-binding capacity [TIBC], transferrin), serum vitamin B12, and serum folate levels. The nutritional background at baseline may be captured, and its improvement with treatment and supplementation may be charted and reported.

To evaluate the overall cost-effectiveness of CHL, including medication, monitoring, and adverse event management costs. The direct cost of various medicines/transfusions/admissions/procedures related to Late GI bleeding and its complications incurred by patients will be collated from electronic charts of patients and estimated to be compared. Cost effectiveness will also be estimated and compared using EQ-5D-5L questionnaire. This measures health in five domains namely mobility, self-care, usual activities, pain/discomfort and anxiety/depression. These responses are converted to a single index score (utility) which are then multiplied by time spent in that state to estimate the QALY. The exploratory analysis of estimating recovering quality of life utility index and incremental cost effectiveness ratio may be defined and estimated with available data.

To monitor and compare the number and frequency of blood transfusions required post-treatment between study arms during both parts.

To assess health-related quality of life using validated patient-reported outcome measures, QLQ C30 Questionnaires at baseline and at every Visits ( 2-6 month) (+/- 1 month). Patient-reported outcomes will be analysed after obtaining the responses. EORTC questionnaires are available in Hindi, Marathi and Bangla languages. They will be provided to the literate patient in the language of their choice by the study coordinator for filling. In case of any difficulty in understanding any word or sentence, it would be explained by the study team. In the case of illiterate patients, patient relatives will be allowed to fill the form on the patient's behalf based on the patient's responses to the questions. The forms will be filled during the waiting period in OPD or for other investigations. Other scores are available only in English and will be filled by the patient directly if the patient or relatives know how to read and write English, or else

To assess health-related quality of life using validated patient-reported outcome measures EORTC questionnaire PRT-20 at baseline, one month on treatment (+/-1 week), 3 months (completion of study intervention; +/-2 weeks), and 6 months (+/- 1month), and then 6 monthly till two years (+/- 1 month).

To assess health-related quality of life using validated patient-reported outcome measures questionnaire LENT-SOMA at baseline, one month on treatment (+/-1 week), 3 months (completion of study intervention; +/-2 weeks), and 6 months (+/- 1month), and then 6 monthly till two years (+/- 1 month).

To assess health-related quality of life using validated patient-reported outcome measures questionnaire EQ-5D-5L at baseline, one month on treatment (+/-1 week), 3 months (completion of study intervention; +/-2 weeks), and 6 months (+/- 1month), and then 6 monthly till two years (+/- 1 month).

To evaluate the frequency of breakthrough or recurrent GI bleeding episodes.

To evaluate the need for re-initiation of Nrf2 therapy or alternative adjunctive treatments such as CHL.